scholarly journals The diabetes-linked transcription factor PAX4 promotes β-cell proliferation and survival in rat and human islets

2004 ◽  
Vol 167 (6) ◽  
pp. 1123-1135 ◽  
Author(s):  
Thierry Brun ◽  
Isobel Franklin ◽  
Luc St-Onge ◽  
Anna Biason-Lauber ◽  
Eugene J. Schoenle ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Cell Function ◽  
Fold Increase ◽  
Human Islets ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Β Cell ◽  
Atp Production ◽  
Adult Rat

The mechanism by which the β-cell transcription factor Pax4 influences cell function/mass was studied in rat and human islets of Langerhans. Pax4 transcripts were detected in adult rat islets, and levels were induced by the mitogens activin A and betacellulin. Wortmannin suppressed betacellulin-induced Pax4 expression, implicating the phosphatidylinositol 3-kinase signaling pathway. Adenoviral overexpression of Pax4 caused a 3.5-fold increase in β-cell proliferation with a concomitant 1.9-, 4-, and 5-fold increase in Bcl-xL (antiapoptotic), c-myc, and Id2 mRNA levels, respectively. Accordingly, Pax4 transactivated the Bcl-xL and c-myc promoters, whereas its diabetes-linked mutant was less efficient. Bcl-xL activity resulted in altered mitochondrial calcium levels and ATP production, explaining impaired glucose-induced insulin secretion in transduced islets. Infection of human islets with an inducible adenoviral Pax4 construct caused proliferation and protection against cytokine-evoked apoptosis, whereas the mutant was less effective. We propose that Pax4 is implicated in β-cell plasticity through the activation of c-myc and potentially protected from apoptosis through Bcl-xL gene expression.

scholarly journals The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets

PLoS Genetics ◽  
2016 ◽  
Vol 12 (12) ◽  
pp. e1006466 ◽  
Author(s):  
Mark P. Keller ◽  
Pradyut K. Paul ◽  
Mary E. Rabaglia ◽  
Donnie S. Stapleton ◽  
Kathryn L. Schueler ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Human Islets ◽  
Β Cell

scholarly journals Genistein Induces Pancreatic β-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3026-3037 ◽  
Author(s):  
Zhuo Fu ◽  
Wen Zhang ◽  
Wei Zhen ◽  
Hazel Lum ◽  
Jerry Nadler ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Function ◽  
Herbal Medicines ◽  
Human Islets ◽  
Pancreatic Β Cell ◽  
Diabetic Mice ◽  
Β Cell ◽  
Β Cell Function ◽  
17Β Estradiol ◽  
Multiple Signaling

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic β-cell function are very limited. In the present study, we investigated the effect of genistein on β-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet β-cell proliferation after 24 h of incubation, with 5 μm genistein inducing a maximal 27% increase. The effect of genistein on β-cell proliferation was neither dependent on estrogen receptors nor shared by 17β-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated β-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for β-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet β-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic β-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway.

scholarly journals Cyclin C stimulates β-cell proliferation in rat and human pancreatic β-cells

2015 ◽  
Vol 308 (6) ◽  
pp. E450-E459 ◽  
Author(s):  
Margarita Jiménez-Palomares ◽  
José Francisco López-Acosta ◽  
Pablo Villa-Pérez ◽  
José Luis Moreno-Amador ◽  
Jennifer Muñoz-Barrera ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Brdu Incorporation ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cyclin C ◽  
Β Cell Function

Activation of pancreatic β-cell proliferation has been proposed as an approach to replace reduced functional β-cell mass in diabetes. Quiescent fibroblasts exit from G0 (quiescence) to G1 through pRb phosphorylation mediated by cyclin C/cdk3 complexes. Overexpression of cyclin D1, D2, D3, or cyclin E induces pancreatic β-cell proliferation. We hypothesized that cyclin C overexpression would induce β-cell proliferation through G0 exit, thus being a potential therapeutic target to recover functional β-cell mass. We used isolated rat and human islets transduced with adenovirus expressing cyclin C. We measured multiple markers of proliferation: [3H]thymidine incorporation, BrdU incorporation and staining, and Ki67 staining. Furthermore, we detected β-cell death by TUNEL, β-cell differentiation by RT-PCR, and β-cell function by glucose-stimulated insulin secretion. Interestingly, we have found that cyclin C increases rat and human β-cell proliferation. This augmented proliferation did not induce β-cell death, dedifferentiation, or dysfunction in rat or human islets. Our results indicate that cyclin C is a potential target for inducing β-cell regeneration.

Human islet expression levels of Prostaglandin E2 synthetic enzymes, but not prostaglandin EP3 receptor, are positively correlated with markers of β-cell function and mass in non-diabetic obesity

2021 ◽  
Author(s):  
Nathan A. Truchan ◽  
Rachel J. Fenske ◽  
Harpreet K. Sandhu ◽  
Alicia M. Weeks ◽  
Chinmai Patibandla ◽  
...  
Keyword(s):  
Cell Function ◽  
Human Islets ◽  
Gene Symbol ◽  
Arachidonic Acid Metabolite ◽  
Prostaglandin E ◽  
Mrna Levels ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Cell Function ◽  
Islet Size

AbstractWe and others previously reported increased signaling through the Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor (GPCR) for the arachidonic acid metabolite, prostaglandin E2 (PGE2), is associated with β-cell dysfunction of type 2 diabetes (T2D). Yet, the relationship between PGE2 production and signaling and β-cell function during the progression to T2D remains unclear. In this work, we assessed gene expression from a panel of cadaveric human islets from 40 non-diabetic donors with BMI values spanning the spectrum from lean to high-risk obesity. Interleukin-6 (gene symbol: IL6) and cyclooxygenase-2 (COX-2) (gene symbol: PTGS2) mRNA levels were positively correlated with donor body mass index (BMI), while EP3 (gene symbol: PTGER3) was not. IL6 was itself strongly correlated with PTGS2 and all but one of the other PGE2 synthetic pathway genes tested. About half of the islet preparations were used in glucose-stimulated- and incretin-potentiated insulin secretion assays using an EP3-specific antagonist, confirming functionally-relevant up-regulation of PGE2 production. Islets from obese donors showed no inherent β-cell dysfunction and were at least equally as glucose- and incretin-responsive as islets from non-obese donors. Furthermore, insulin content, a marker of islet size known to be associated with donor BMI, was also significantly and positively correlated with islet PTGS2 expression. We conclude up-regulated islet PGE2 production and signaling may be a necessary part of the β-cell adaption response, compensating for obesity and insulin resistance. Analysis of plasma PGE2 metabolite levels from a clinical cohort reveal these findings are not in conflict with the concept of further elevations in PGE2 production contributing to T2D-related β-cell dysfunction where islet EP3 expression has also been up-regulated.Graphical Abstract

scholarly journals Compromised Function of the Pancreatic Transcription Factor PDX1 in a Lineage of Desert Rodents

2021 ◽  
Author(s):  
Yichen Dai ◽  
Sonia Trigueros ◽  
Peter W. H. Holland
Keyword(s):  
Transcription Factor ◽  
Gene Conversion ◽  
Cell Function ◽  
Protein A ◽  
Gene Promoter ◽  
Homeodomain Protein ◽  
Β Cell ◽  
Desert Rodents ◽  
Biased Gene Conversion ◽  
Β Cell Function

AbstractGerbils are a subfamily of rodents living in arid regions of Asia and Africa. Recent studies have shown that several gerbil species have unusual amino acid changes in the PDX1 protein, a homeodomain transcription factor essential for pancreatic development and β-cell function. These changes were linked to strong GC-bias in the genome that may be caused by GC-biased gene conversion, and it has been hypothesized that this caused accumulation of deleterious changes. Here we use two approaches to examine if the unusual changes are adaptive or deleterious. First, we compare PDX1 protein sequences between 38 rodents to test for association with habitat. We show the PDX1 homeodomain is almost totally conserved in rodents, apart from gerbils, regardless of habitat. Second, we use ectopic gene overexpression and gene editing in cell culture to compare functional properties of PDX1 proteins. We show that the divergent gerbil PDX1 protein inefficiently binds an insulin gene promoter and ineffectively regulates insulin expression in response to high glucose in rat cells. The protein has, however, retained the ability to regulate some other β-cell genes. We suggest that during the evolution of gerbils, the selection-blind process of biased gene conversion pushed fixation of mutations adversely affecting function of a normally conserved homeodomain protein. We argue these changes were not entirely adaptive and may be associated with metabolic disorders in gerbil species on high carbohydrate diets. This unusual pattern of molecular evolution could have had a constraining effect on habitat and diet choice in the gerbil lineage.

Effects of glucose and d-3-hydroxybutyrate on human pancreatic islet cell function

1985 ◽  
Vol 68 (5) ◽  
pp. 567-572 ◽  
Author(s):  
C. J. Rhodes ◽  
I. L. Campbell ◽  
T. M. Szopa ◽  
T. J. Biden ◽  
P. D. Reynolds ◽  
...  
Keyword(s):  
Insulin Release ◽  
Human Tissue ◽  
Islet Cell ◽  
Cell Function ◽  
Human Islets ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Sigmoidal Curve ◽  
Β Cell Function ◽  
Islet Cell Function

1. β-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. 2. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. 3. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of d-3-hydroxybutyrate/l. 4. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. 5. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. 6. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.

scholarly journals Furin controls β cell function via mTORC1 signaling

2020 ◽  
Author(s):  
Bas Brouwers ◽  
Ilaria Coppola ◽  
Katlijn Vints ◽  
Bastian Dislich ◽  
Nathalie Jouvet ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Cell Function ◽  
Mammalian Target Of Rapamycin ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Differential Proteomics ◽  
Atpase Subunit ◽  
Proteolytic Activation ◽  
Mtorc1 Signaling

AbstractFurin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the essential V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction.

scholarly journals The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets

2016 ◽  
Vol 5 (10) ◽  
pp. 988-996 ◽  
Author(s):  
Kevin Vivot ◽  
Valentine S. Moullé ◽  
Bader Zarrouki ◽  
Caroline Tremblay ◽  
Arturo D. Mancini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
G Protein ◽  
Human Islets ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Β Cell

scholarly journals NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Idil I. Aigha ◽  
Essam M. Abdelalim
Keyword(s):  
Transcription Factor ◽  
Cell Function ◽  
Disease Modeling ◽  
Critical Role ◽  
Cell Mass ◽  
Cell Development ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Abstract Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.

scholarly journals Role of renal nerves for the expression of renin in adult rat kidney

1994 ◽  
Vol 266 (5) ◽  
pp. F738-F745 ◽  
Author(s):  
S. Holmer ◽  
B. Rinne ◽  
K. U. Eckardt ◽  
M. Le Hir ◽  
K. Schricker ◽  
...  
Keyword(s):  
Renal Denervation ◽  
Rat Kidney ◽  
Fold Increase ◽  
Renal Nerves ◽  
Mrna Levels ◽  
Adult Rats ◽  
Adult Rat ◽  
Mrna Content ◽  
Renin Mrna ◽  
Renal Innervation

Utilizing a combination of mechanical and chemical unilateral denervation, we have examined the relevance of renal innervation for the expression of renin in kidneys of adult rats. Renal denervation led to a reduction by 57 +/- 4% of renin-containing areas in denervated kidneys as quantitated by morphometry of kidney sections immunoreactive against a polyclonal antirenin antibody. Preprorenin mRNA content in the denervated kidneys fell to 46 +/- 7% of the contralateral innervated kidneys. Treatment of rats with the beta 1-adrenoreceptor antagonist metoprolol (100 mg.kg-1.day-1) for 2 days decreased renal renin mRNA levels to 71% of control levels. Unilateral renal denervation led to a further decrease of renin mRNA levels also in metoprolol-treated animals to 60% of the values found in the contralateral kidneys. Hypotensive hemorrhage led to a 1.4-fold increase of renin mRNA in the kidneys of sham-treated animals. In unilaterally denervated rats renin mRNA increased to levels similar to those in sham-operated animals in both denervated and in contralateral innervated kidneys in response to bleeding. As a consequence, the ratio of abundance of renin mRNA in the denervated to the innervated kidneys rose to 86 +/- 7%. Pretreatment of the animals with metoprolol, on the other hand, prevented the rise of renin mRNA in response to hypotensive hemorrhage. Our findings suggest that in the adult organism renal neural input significantly contributes to the expression of renin under basal conditions, while it appears to be of less importance for stimulation of renin gene expression by severe blood loss.

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